One hundred years of clostridial butanol fermentation

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FEMS Microbiology Letters, 363, 2016, fnw001 doi: 10.1093/femsle/fnw001 Advance Access Publication Date: 6 January 2016 Minireview

M I N I R E V I E W – Biotechnology & Synthetic Biology

One hundred years of clostridial butanol fermentation Hyeon Gi Moon1 , Yu-Sin Jang1,2 , Changhee Cho1 , Joungmin Lee1,2 , Robert Binkley1 and Sang Yup Lee1,2,3,∗ 1

Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 Plus Program), Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, Korea Advanced Institute of Science and Technololgy (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea, 2 BioProces Engineering Research Center, KAIST, Daejeon 34141, Republic of Korea and 3 Bioinformatics Research Center, KAIST, Daejeon 34141, Republic of Korea ∗

Corresponding author: Department of Chemical and Biomolecular Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. Tel: +82-42-350-3930; Fax: +82-42-350-3910; E-mail: [email protected] One sentence summary: This minireview revisits the 100-years’ achievements in clostridial butanol fermentation. Editor: Michael Sauer

ABSTRACT Butanol has been widely used as an important industrial solvent and feedstock for chemical production. Also, its superior fuel properties compared with ethanol make butanol a good substitute for gasoline. Butanol can be efficiently produced by the genus Clostridium through the acetone–butanol–ethanol (ABE) fermentation, one of the oldest industrial fermentation processes. Butanol production via industrial fermentation has recently gained renewed interests as a potential solution to increasing pressure of climate change and environmental problems by moving away from fossil fuel consumption and moving toward renewable raw materials. Great advances over the last 100 years are now reviving interest in bio-based butanol production. However, several challenges to industrial production of butanol still need to be overcome, such as overall cost competitiveness and development of higher performance strains with greater butanol tolerance. This minireview revisits the past 100 years of remarkable achievements made in fermentation technologies, product recovery processes, and strain development in clostridial butanol fermentation through overcoming major technical hurdles. Keywords: butanol; ABE; Clostridium; fermentation; solvent; 100 years

INTRODUCTION The development of an acetone–butanol–ethanol (ABE) fermentation platform initially began as a response to a high demand for acetone production in the early 20th century, particularly during World War I (1914–18). Large amounts of acetone were urgently needed in England as solvent for the production of the explosive cordite (Killeffer 1927; Gabriel 1928; Jones and Woods 1986). Due to this demand, the first industrial-scale ABE fermentations utilizing the Weizmann process began operation in 1916. This Weizmann process, which utilized Clostridium acetobutylicum, was able to produce 3000 tons of acetone

and 6000 tons of butanol within the next two years (Gabriel 1928; Jones and Woods 1986). Since then, various fermentation processes have been developed in order to satisfy the ever increasing demands of butanol and overcome the inherent process limitations including low butanol production, solvent toxicity, fermentation stability and high operation cost (Beesch 1952; ¨ ¨ 1985; Jones and Woods 1986; Maddox 1989). Although Haggstr om the prominence of ABE fermentation declined in the middle of the 20th century with rapid advances in petrochemical industry, bio-butanol production via ABE fermentation has received renewed interest as it may contribute to solving many of today’s

Received: 13 December 2015; Accepted: 30 December 2015  C FEMS 2016. All rights reserved. For permissions, please e-mail: [email protected]

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FEMS Microbiology Letters, 2016, Vol. 363, No. 3

Figure 1. Timeline of notable events and advances in butanol fermentation from 1916 to 2015. Upper side of the timeline lists major events in butanol production history, while more specific events are summarized below the timeline. Event colors represent: green, first isolation of representative butanol producing clostridial strains; blue, major technological advancements in fermentation and/or recovery processes; black, key technologies for metabolic engineering of clostridia; and red, representative clostridial strains showing notable butanol production. Detailed description on the performance of notable strains is shown in Table 1. Abbreviations: ABE, acetone-butanol-ethanol; Bsu, B. subtilis; Cac, C. acetobutylicum; Cbe, C. beijerinckii; Cpa, C. pasteurianum; Csa, C. saccharoperbutylacetonicum; Cty, C. tyrobutyricum; Eco, E. coli; KD, knockdown; and KO, knockout.

problems, including exhaustion of natural resources, climate change, environmental pollution and global warming. The most widely implemented butanol production platform utilizes the genus Clostridium through ABE fermentation (Durre 2007; Lee et al. 2008b; Jang et al. 2012c; Cho et al. 2015b). Recent research has been performed which investigates the combination of modifications to fermentation processes and strain development using metabolic engineering in order to obtain the levels of butanol titer, yield and productivity required to meet industrial competitiveness. The following sections focus on the developments of butanol fermentation and genetic/metabolic engineering strategies employed in the last 100 years which have resulted in remarkably enhanced butanol production. The notable events and advances in butanol fermentation are shown in Fig. 1 and Table 1.

BRIEF HISTORY UNTIL 1970 Prior to the patent expiration in 1936, the Weizmann process was a common industrial fermentation procedure used to produce acetone and butanol. Several papers describe in detail the Weizmann process at the over 150 000 liter-scale (Killeffer 1927; Gabriel 1928; Gabriel and Crawford 1930). This process generally involved a batch process where cooked maize mash was used as the primary fermentation medium and operated at 37◦ C. In 1936,

a more economical process was established (Beesch 1952), which utilized molasses or other industrial sugars as carbon sources and the decreased fermentation temperature of 31◦ C. Fermentation research progressed rapidly and made ABE fermentation more economical. Other advancements included use of cheaper carbon source, lower fermentation temperature, improved utilization of residual sugars, decreased incidents of contamination, and increased butanol selectivity. Until the 1950’s, ABE fermentation supplied ∼66% and 10% of the world’s supply of butanol and acetone, respectively (Durre 2008). An increase in the price of the carbon sources and the rapid developments in the petrochemical industry for highly efficient butanol production led to the decline in the use of ABE fermentation. This led to a significant decline in research on ABE fermentation as well as the closing of many ABE fermentation facilities except for a few in countries including South Africa, the former Soviet Union, Egypt and China (Zverlov et al. 2006; Chiao and Sun 2007; Durre 2007; Jiang et al. 2015). The detailed early history of the ABE fermentation is well described by Jones and Woods (1986).

THE REVIVAL WITH ADVANCED FERMENTATION PROCESS The oil crisis in the 1970s renewed interest in butanol as a possible alternative to petrochemical fuel. Before the advent

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C. acetobutylicum ATCC 824/pfkA+pykA C. acetobutylicum BKM19 C. acetobutylicum ATCC 824 and B. subtilis DSM 4451 C. acetobutylicum P262 C. acetobutylicum IFP 904 C. acetobutylicum DSM792 C. beijerinckii NCIMB 8052

C. acetobutylicum HKKO C. acetobutylicum mutant B C. acetobutylicum PJC4BK C. acetobutylicum SolRH(pTAAD)

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Spoilage date palm fruits

Sago starch

Jerusalem artichoke Sugar mixture Glucose

W

W

M

W

W

Glucose

E, M

Glucose

E

Glucose

Glucose

E

E

Glucose

Glucose

E

E

Glucose

E

Glucose

Glucose

W

E

Glucose

W

Glucose

W

C. acetobutylicum DSM792 C. acetobutylicum XY16 C. acetobutylicum ATCC 824(pGROE1) C. acetobutylicum BEKW(pPthlAAD∗∗ )

Glucose

W

C. acetobutylicum ATCC 824 C. acetobutylicum DSM 1731

Substrate

Typea

Name

Strain

Batch

Continuous

Batch

Batch

Batch

Continuous

Fed-batch

Batch

Batch

Batch

Batch

Batch

Batch

Continuous

Continuous

Continuous

Batch

Type

Table 1. Representative studies of high level butanol production.

42 (20)

0.12 (0.1)

6 (4)

0.25

2 (0.88)

1 (0.4)

5 (2)

2 (1.8) or 5 (4) 2 (1.5) or 5 (4)

5.5 (5)

0.25 (0.15)

5 (2)

2 (1.5)

5 (3)

2 (first) and 5 (second) 0.12 (0.1)

5 (4)

Scale (working volume; L)

83.5

600

33

88

72

935

9.2

0.17

0.28c

8.1c

0.11

12.1c

0.45

0.25

–b 0.23

0.3

10.7

0.19

0.40

0.17

0.21

0.33

0.31

–b –b

0.21

0.38

0.33

0.25

0.2

0.29

14.8

21.6

21.7

11.9

19.1

17.6

–b

102

16.7

17.8

18.2

18.9

54

86

48

57

0.14

13.7c

–b

–b

5.7c

–b 17.1

0.40c

7.2c

600

120

–b

12.6

–b

∼0.33

11.3c

∼0.16

∼9.8

30

Productivity (g L−1 h−1 )

0.31c

Yield (g g−1 )

Titer (g L−1 )

Time (h)

Fermentation

Immobilized

Addition of yeast extract and NH4 NO3

Coculture, addition of yeast extract and NH4 NO3

Cell recycle

Overexpression of the adhE1 gene and disruption of solR gene Overexpression of the pfkA and pykA genes

Disruption of the buk gene

Overexpression of the groESL operon genes Overexpression of the mutant adhE1 gene and disruption of pta and buk genes Disruption of the CAC3319 gene Disruption of the solR gene

Immobilized

Immobilized

Two-stage

Comment

(Marchal, Blanchet and Vandecasteele 1985) (Survase, van Heiningen and Granstrom 2012) (Formanek, Mackie and Blaschek 1997)

(Madihah et al. 2001)

(Abd-Alla and El-Enany 2012)

(Jang et al. 2013a)

(Ventura, Hu and Jahng 2013)

(Harris et al. 2001)

(Harris et al. 2000)

(Nair et al. 1999)

(Xu et al. 2015)

(Tomas, Welker and Papoutsakis 2003) (Jang et al. 2012b)

(Survase, van Heiningen and Granstrom 2012) (Kong et al. 2015)

(Bahl, Andersch and Gottschalk 1982)

(Desai et al. 1999)

Reference

Moon et al. 3

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Glucose

Glucose

Bagasse

Cassava chips

Cassava starch

Glucose

Mannitol

Maltose

M W

W

W

W

W

W

W

W

E

E

C. beijerinckii BA101 C. pasteurianum ATCC 6013 C. pasteurianum DSMZ 525 C. pasteurianum MBEL GLY2 C. saccharoperbutylacetonicum N1-4 C. saccharoperbutylacetonicum N1-4 C. saccharoperbutylacetonicum ATCC 27022 C. saccharoperbutylacetonicum N1-4 C. saccharoperbutylacetonicum N1-4 C. tyrobutyricum ATCC 25755 C. tyrobutyricum CTpM2 C. tyrobutyricum(ack)pGluI

Cassava flour

Glucose Maltodextrin

Batch

Fed-batch

Fed-batch

Batch

Batch

Batch

Continuous

Batch

Continuous

Batch

Continuous Batch

Batch

Continuous Batch

Batch

Type

b

Each word indicate as W: Wild type; E: Engineered; M: Mutant. Values not available. c Values reported are total solvent.

a

Glucose and glycerol Glycerol

M

C. beijerinckii BA101

M

Sugar Glycerol

M M

C. beijerinckii BA101 C. beijerinckii BA101

Glucose

M

C. beijerinckii BA101

Substrate

Typea

Name

Strain

Table 1. (Continued).

1 (0.6)

2 (1)

5 (2)

1

1

43

17.3

20.5

–b

–b 64

16.9

16.4

16.5

48

36

60

–b

0.17

0.33

–b

0.35

0.26

0.28

–b

8.6c

207

0.43

14

0.4

0.32

–b

0.35

0.46

0.28

7.6c

–b

7.8

–b

–b

0.42

16.2c 0.27

0.31

15.8c 0.26

0.38

Productivity (g L−1 h−1 )

0.23

–b 0.11

8.6

21.1

–b 10.0

0.43

0.38c 0.35

7.9c 18.6 25.7

0.32

Yield (g g−1 )

18.6

Titer (g L−1 )

Fermentation

710

1

0.5 (0.3)

1 (0.4)

50

–b 48

–b 5 (2) 2 (1.5)

83

600 72

49

Time (h)

5 (4)

0.02 42 (20)

42 (20)

Scale (working volume; L)

Overexpression of the adhE2 gene No antibiotics

Addition of butyric acid

Cell recycle

Cell recycle

Immobilized

Immobilized

Comment

(Yu et al. 2015)

(Yu et al. 2012)

(Liu, Zhu and Yang 2006)

(Thang, Kanda and Kobayashi 2010)

(Thang, Kanda and Kobayashi 2010)

(Soni, Das and Ghose 1982)

(Tashiro et al. 2005)

(Malaviya, Jang and Lee 2012) (Tashiro et al. 2004)

(Formanek, Mackie and Blaschek 1997) (Qureshi et al. 2000) (Formanek, Mackie and Blaschek 1997) (Lepiz-Aguilar et al. 2013) (Lienhardt et al. 2002) (Malaviya, Jang and Lee 2012) (Sabra et al. 2014)

Reference

4 FEMS Microbiology Letters, 2016, Vol. 363, No. 3

Moon et al.

of metabolic engineering, most studies focused optimizing fermentation parameters such as medium composition, nutrient limitation and feeding profiles, pH control, cell density and gas transfer considerations in order to increase production (Jones and Woods 1986; Junelles et al. 1988). The following subsections discuss several notable advancements in the production process including substrate selection, coculture, cell immobilization, multistage fermentation, cell recycle fermentation and in situ product recovery, which made contributions in overcoming many of the limitations in butanol fermentation.

Substrates Substrate selection can have a strong impact on fermentation performance and overall production cost. Identifying costeffective substrates is vital for the economical ABE fermentation. Initially, low-cost agricultural wastes such as bagasse and rice straw were hydrolyzed by a mixed culture of two cellulolytic fungi to make fermentable sugars (Soni, Das and Ghose 1982). The pretreated bagasse hydrolyzates were used to produce solvent using C. saccharoperbutylacetonicum, which produced 16.5 g L−1 of butanol (Table 1; Soni, Das and Ghose 1982; Tashiro et al. 2004). Similarly, various substrates have been employed for butanol production (Table 1): Jerusalem artichoke juice (Marchal, Blanchet and Vandecasteele 1985); maltodextrin (Formanek, Mackie and Blaschek 1997); Sago starch (Madihah et al. 2001); cassava starch and cassava chips (Thang, Kanda and Kobayashi 2010); enzymatically hydrolyzed cassava flour (Lepiz-Aguilar et al. 2013). The use of multiple carbon sources was also investigated. In a batch fermentation utilizing a mixture of (1:1, w/w) glucose and glycerol, a byproduct of biodiesel production, C. pasteurianum produced 21 g L−1 of butanol with a yield of 0.23 g g−1 (Sabra et al. 2014). A more detailed comparison of fermentation results utilizing various strains and carbon sources can be found in several review papers (Jang et al. 2012c; Schiel-Bengelsdorf et al. 2013; Li, Baral and Jha 2014; Zheng et al. 2015). As the clostridial strain is able to utilize a wide range of substrates, identification of locally or logistically available costeffective carbon sources is important depending upon the country of operation.

Coculture and multistage fermentation Coculture fermentations have been employed utilizing different microbial strains (Bader et al. 2010) in order to expand substrate utilization (Nakayama et al. 2011), to eliminate inhibition factors (Abd-Alla and El-Enany 2012) and to enhance butanol titer (Li et al. 2013). The cellulose-utilizing C. thermocellum strain was cocultured with a butanol-producing C. saccharoperbutylacetonicum strain and 5.8 g L−1 of butanol was produced with a yield of 0.15 g g−1 microcrystalline cellulose (Nakayama et al. 2011). In another study, anaerobic condition was maintained by coculturing Bacillus subtilis DSM 4451 and C. acetobutylicum ATCC 824 (Abd-Alla and El-Enany 2012). In fed-batch coculture of the immobilized C. tyrobutyricum cells (butyric acid producer) and C. beijerinckii cells (butanol producer), 12.8 g L−1 butanol was produced with a yield of 0.16 g g−1 glucose (Li et al. 2013). Luo et al. (2015) reported that production of 15.7 g L−1 of butanol with a yield of 0.23 g g−1 glucose by coculturing C. acetobutylicum and Saccharomyces cerevisiae with 4 g L−1 of butyrate addition. Positive effects of coculturing with S. cerevisiae, including amino acids assimilation, substrate consumption and NADH regeneration, were suggested (Luo et al. 2015). The use of multiple fermentation stages has also been considered as a method to convert whole substrates into solvent

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since the genus Clostridium has two distinct metabolic phases, acidogenic and solventogenic phases, where fermentation conditions can be targeted for each phase. In a study, a single-stage phosphate-limited continuous fermentation held at 37◦ C and a dilution rate of 0.125 h−1 resulted in 9.6 g L−1 of butanol with 0.16 g g−1 of yield with 80% of glucose conversion. When a second stage was introduced operating at 33◦ C and 0.03 h−1 of dilution rate, butanol production was augmented to 12.6 g L−1 with 0.21 g g−1 of yield and 87.5% of glucose conversion (Bahl, Andersch and Gottschalk 1982). The addition of more stages (e.g. five-stage fermentation) did not lead to enhanced solvent production (Afschar et al. 1985). Further works optimizing pH and dilution rates enhanced both the stability and productivity of two-stage continuous fermentation process (Godin and Engasser 1988; Godin and Engasser 1990). A methodical investigation along with careful optimization of multistage fermentation has potential to further increase productivity and yield of butanol.

Immobilization and cell recycling Cell immobilization and cell recycling techniques are advantageous in achieving high butanol productivity as these methods facilitate increased biomass levels during continuous fermentation. Cell immobilization makes it possible to maintain higher cell densities by reducing cell loss due to washout and is compatible with many reactor configurations, including continuous stirred tank reactors (CSTR), packed-bed reactor, fluidized-bed reactor and gas-lift loop reactor (Maddox 1989). Initial investigation utilized calcium alginate as the immobilizing agent for C. acetobutylicum vegetative cells and spores in continuous fermentations. Using glucose as a substrate, the immobilized C. acetobutylicum spores resulted in butanol productivity of 0.48– 0.64 g L−1 h−1 , notably higher than 0.29–0.39 g L−1 h−1 ob¨ ¨ tained by a typical batch fermentation (Haggstr om and Molin 1980). Other cost effective materials for immobilization were studied to improve butanol productivity in continuous fermentation including: κ-carrageenan, chitosan, beechwood shaving, coke, bonechar, sponge, clay brick and wood pulp (Forberg and Haggstrom 1985; Frick and Schugerl 1986; Qureshi and Maddox 1987; Welsh, Williams and Veliky 1987; Park, Okos and Wankat 1989; Qureshi et al. 2000; Survase, van Heiningen and Granstrom 2012). In a continuous fermentation of C. beijerinckii BA101 using clay brick packed bed reactor from glucose, ABE productivity of 15.8 g L−1 h−1 was achieved at a dilution rate of 2.0 h−1 (Qureshi et al. 2000). When pervaporation was coupled with a clay brick biofilm reactor using immobilized C. beijerinckii BA 101, solvent productivity of 16.2 g L−1 h−1 was achieve at a dilution rate of 2.0 h−1 (Lienhardt et al. 2002). C. acetobutylicum DSM 792 cells immobilized on wood pulp showed an ABE productivity of 13.7 g L−1 h−1 from glucose at a dilution rate of 1.9 h−1 (Survase, van Heiningen and Granstrom 2012). Chemically modified sugarcane bagasse has been recently used to improve adsorption capacity and bonding strength in the immobilization of C. acetobutylicum cells (Kong et al. 2015); the ABE productivity of 11.3 g L−1 h−1 could be achieved using the immobilized C. acetobutylicum XY16 cells (Kong et al. 2015). Cell recycle techniques have also demonstrated an ability to achieve high butanol productivity. In a continuous fermentation with cell recycling using a microporous polypropylene module, C. acetobutylicum ATCC 824 showed ABE production with a productivity of 5.4 g L−1 h−1 from glucose at a dilution rate of 0.64 h−1 (Afschar et al. 1985). When ultramembrane filters and

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hollow-fiber membranes were used for cell recycling of C. acetobutylicum ATCC 824, ABE productivities of 4.34 and 6.5 g L−1 h−1 could be achieved at dilution rates of 0.33 and 0.5 h−1 , respectively, from glucose (Ferras, Minier and Goma 1986; Pierrot, Fick and Engasser 1986). Clostridium saccharoperbutylacetonicum N1-4 strain showed an ABE productivity of 11.0 g L−1 h−1 at a dilution rate of 0.85 h−1 from glucose in a continuous fermentation with cell recycling using hollow-fiber membrane (Tashiro et al. 2005). When C. saccharoperbutylacetonicum cells were recycled with bleeding to avoid heavy bubbling and broth outflow, an ABE productivity of 7.6 g L−1 h−1 was achieved at a dilution rate of 0.71–0.74 h−1 and a bleeding rate of 0.11–0.16 h−1 (Tashiro et al. 2005). In another study, C. pasteurianum MBEL GLY2, a mutant strain derived from C. pasteurianum ATCC 6013, resulted in a solvent productivity of 8.3 g L−1 h−1 (butanol productivity of 7.8 g L−1 h−1 ) at a dilution rate of 0.9 h−1 using glycerol as the sole carbon source in a hollow-fiber membrane cell recycle bioreactor that was successfully operated for 710 h (Malaviya, Jang and Lee 2012). Similarly, the hollow-fiber membrane cell recycle fermentation of C. acetobutylicum BKM19, a random mutant of PJC4BK strain (Green et al. 1996; Jang, Malaviya and Lee 2013a) resulted in the ABE productivity of 21.1 g L−1 h−1 (butanol productivity of 10.7 g L−1 h−1 ) at a dilution rate of 0.86 h−1 with a bleeding rate of 0.04 h−1 (Jang, Malaviya and Lee 2013a). Thanks to the advances in immobilization and membrane technologies together with the availability of low-cost immobilization and membrane materials, cell immobilization and/or cell recycle-coupled fermentations will be increasingly used for more economical production of butanol through achieving high productivity. Such systems can be efficiently coupled with in situ butanol recovery to overcome butanol toxicity, as will be described below.

Fermentation process with in situ recovery Butanol is highly toxic to all microorganisms, including clostridia, and at high concentrations can lead to reduced substrate consumption and decreased overall cellular metabolism. Overcoming butanol toxicity has become a major challenge in the economical production of butanol with fed-batch cultivation demonstrating little to no advantage when compared with batch fermentation for butanol production (Fond et al. 1984). To overcome this problem in terms of bioprocess, various methods of in situ recovery processes were extensively studied to further enhance butanol fermentation: gas stripping, liquid-liquid extraction, perstraction, vacuum extraction, pervaporation and adsorption (Abdehagh, Tezel and Thibault 2014; Xue et al. 2014). Gas stripping can be applied to batch, fed-batch (Qureshi, Maddox and Friedl 1992; Ezeji, Qureshi and Blaschek 2004; Lee et al. 2012a), continuous (Ennis, Qureshi and Maddox 1987; Mollah and Stuckey 1993; Setlhaku et al. 2013) and immobilized cell fermentations (Ennis, Qureshi and Maddox 1987; Qureshi and Maddox 1991; Xue et al. 2013; Cai et al. 2015; Xue et al. 2016). The possibility of employing in situ gas stripping for butanol recovery was examined during the batch fermentation of C. saccharobutylicum P262 using sulfate whey permeate as a substrate (Ennis et al. 1986). Compared to batch fermentation, application of in situ gas stripping increased the lactose consumption up to 2fold (58.3 versus 29 g L−1 ), with the final butanol concentration and yield of 11.0 g L−1 and 0.19 g g−1 lactose, respectively (Ennis et al. 1986). When this approach was applied to a fed-batch fermentation using the C. beijerinckii BA101 strain, 151.7 g L−1 of butanol could be produced with a yield of 0.30 g g−1 glucose and a productivity of 0.75 g L−1 h−1 (Ezeji, Qureshi and Blaschek 2004). Although the butanol condensate obtained from gas strip-

ping had a greater titer of butanol as compared to the fermentation broth, the condensate still contained a large amount of water, which required additional gas stripping or other separation techniques in order to further concentrate butanol. A two-stage gas stripping fermentation using immobilized cells of C. acetobutylicum JB200 made it possible to obtain highly concentrated butanol (420.3 g L−1 ) from the second stage gas stripping condensate, which was a significant increase over that (175.6 g L−1 ) obtained from the first stage (Xue et al. 2013). More recently, fedbatch fermentation of C. acetobutylicum JB200 coupled with the combination of in situ gas stripping and pervaporation using a carbon nanotube composite material resulted in more concentrated butanol of 521.3 g L−1 (Xue et al. 2016). Although gas stripping has several advantages as a technique for in situ butanol recovery, more studies are needed as its scale up appears still challenging due to increased high gas flow rate and pressure. As an alternative to gas stripping, vacuum enhanced recovery has also been demonstrated to be a possible method to remove butanol from the fermentation medium. An integrated ABE fermentation featuring vacuum product recovery was reported, in which C. beijerinckii P260 produced 45.9 g L−1 (in condensate) with a productivity of 0.34 g L−1 h−1 . This process utilized an intermittent mode operation with vacuum sessions of 1.5 h at intervals of 4 h in order to reduce energy requirement for vacuum formation (Mariano et al. 2011). This process needs to be further investigated for its implementation in large-scale fermentations, as rapid evaporation of water and solvents can cause a sudden decrease of the broth temperature, making temperature control of the fermentation broth unstable during extended operations. In butanol fermentation, utilizing a liquid–liquid extraction is another method to mitigate butanol toxicity with the selection of an appropriate extractant being exceptionally important. For several decades, various extractants for efficiently removing butanol from fermentation broth have been examined, including oleyl alcohol (Roffler, Blanch and Wilke 1987; Qureshi and Maddox 1995), methylated crude palm oil (Ishizaki et al. 1999), biodiesel (Li et al. 2010) and decanol (Bankar et al. 2012). An extraction system of oleyl alcohol and decanol mixture (4:1) integrated with two-stage continuous fermentation of C. acetobutylicum B 5313 utilizing sugarcane bagasse as the cell holding material resulted in 16.9 g L−1 of butanol with a productivity of 1.69 g L−1 h−1 and a yield of 0.23 g g−1 glucose (Bankar et al. 2012). In a later study, two stage immobilized column reactor with wood pulp fiber immobilizing agent and the mixture of oleyl alcohol and decanol (4:1) as extractants was applied to enhance ABE productivity and yield. Fermentation of C. acetobutylicum DSM 792 using this system resulted in 20.3 g L−1 of total solvents (13.6 g L−1 of butanol), a productivity of 10.85 g L−1 h−1 and a yield of 0.38 g g−1 sugar mixture (Bankar et al. 2013). Biodiesel was also investigated as an in situ extractant for ABE fermentation. Supplementation of biodiesel as an extractant at the start of the fermentation at a ratio of 1:1 (25 mL biodiesel added to 25 mL broth) significantly increased butanol production; C. acetobutylicum BCRC 10639 (the same as ATCC 824) in the fed batch operation with glucose feed resulted in 31.4 g L−1 of butanol with a productivity of 0.30 g L−1 h−1 and a yield of 0.31 g g−1 glucose (Yen and Wang 2013). Perstraction is another membrane-based liquid–liquid extraction technique where a membrane is placed between fermentation broth and the extractant. Integrated fermentation with an in situ perstraction module employing silicone membrane and oleyl alcohol, C. acetobutylicum P262 produced 57.8 g L−1 of solvent (37.4 g L−1 of butanol) with a productivity of

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0.24 g L−1 h−1 and a yield of 0.37 g g−1 lactose (Qureshi, Maddox and Friedl 1992). When concentrated lactose/whey permeate solution was used as a substrate, C. acetobutylicum P262 produced 136.6 g L−1 of ABE with a yield of 0.44 g g−1 lactose and productivity of 0.21 g L−1 h−1 (Qureshi and Maddox 2005). When extraction or perstraction is used for butanol recovery, it is important to recover and reuse the extractant for reducing the downstream operating costs. Pervaporation (Kober 1917) was applied to butanol fermentation in 1984 using C. beijerinckii LMD 27.6 (Groot, Vandenoever and Kossen 1984b). In this bioprocess, a fermentation medium within a bioreactor was circulated through a separately equipped pervaporation module containing a silicone membrane while nitrogen was used as a gas stream. In a later study, batch fermentation equipped with the pervaporation module employing silicone tube as a membrane, C. acetobutylicum ATCC 824 strain produced 24.7 g L−1 of butanol (Larrayoz and Puigjaner 1987). The pervaporation process has been adapted for use in continuous cultures employing immobilized clostridial cells (Groot et al. 1984a, 1991; Groot and Luyben 1987; Friedl, Qureshi and Maddox 1991; Izak et al. 2008). In one study utilizing immobilized C. acetobutylicum cells and a pervaporation module, a volumetric solvent productivity of 3.5 g L−1 h−1 was obtained with a solvent yield of 0.39 g g−1 lactose (Friedl, Qureshi and Maddox 1991). In a fed-batch fermentation equipped with the pervaporation module employing the silicalite–silicone composite, C. acetobutylicum ATCC 824 produced 105.4 g L−1 of butanol with a yield of 0.24 g g−1 glucose and a productivity of 0.12 g L−1 h−1 (Qureshi et al. 2001). Recently, poly(ether-block-amide) has been used as a pervaporation membrane in a fed-batch fermentation of C. acetobutylicum ATCC 824 which produced ∼23 g L−1 butanol with a yield of 0.17 g g−1 glucose and a productivity of 0.27 g L−1 h−1 (Yen, Lin and Yang 2012). In addition to poly(ether-block-amide), different types of pervaporation membranes are still under investigation for butanol recovery, including polydimethylsiloxane, polypropylene, polytetrafluoroethylene, composite, liquid and inorganic membranes (Staggs and Nielsen 2015). Adsorption with active carbon, and later with polymer resins, was also investigated as an alternative method for butanol and acetone recovery (Weizmann et al. 1948; Groot and Luyben 1986; Nielsen et al. 1988). When polyvinylpyridine was used as an adsorbent in batch fermentation, C. acetobutylicum ATCC 824 produced 29.8 g L−1 of ABE (17.5 g L−1 of butanol) with a productivity of 0.92 g L−1 h−1 . In a later batch fermentation using poly(styrene-co-divinylbenzene) as an adsorbent, C. acetobutylicum ATCC 824 produced 22.2 g L−1 butanol from 80 g L−1 glucose (Nielsen and Prather 2009). In a fed-batch fermentation using poly(styrene-co-divinylbenzene), C. acetobutylicum ATCC 824 produced 40.7 g L−1 of ABE (27.1 g L−1 of butanol) with a yield of 0.72 g g−1 glucose and a productivity of 0.28 g L−1 h−1 (Wiehn et al. 2014). In the more recent fed-batch fermentation using KAI resin, C. acetobutylicum ATCC 824 produced 96.5 g L−1 of solvents with a yield of 0.33 g g−1 glucose and a productivity of 1.51 g L−1 h−1 , and addition of methyl viologen further improved the titer and yield (Liu et al. 2014). As briefly described above, many advances in butanol production have been made in the last 100 years with respect to fermentation and downstream processing. Further studies are required, such as studies on combinatorial design and integration of various unit operations followed by process optimization. Especially within industrial settings, these advanced studies would likely identify further synergistic effects which could further enhance butanol productivity and yield at lower production costs.

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ERA OF METABOLIC ENGINEERING Although advances in fermentation parameter optimization have been made to overcome many limitations of butanol production, butanol production can be inherently enhanced through metabolic engineering of the production strains (Jang et al. 2012a,d; Cho et al. 2015a). Production of butanol using microorganisms other than clostridia has also been demonstrated recently with comparable performance to clostridial species (Bond-Watts, Bellerose and Chang 2011; Dellomonaco et al. 2011; Shen et al. 2011). Several review papers describe detailed comparison of the characteristics of butanol production by different microorganisms (Jang and Lee 2015; Zheng et al. 2015), and thus, we rather focus on metabolic engineering of clostridia in this paper. The major metabolic pathways for clostridial ABE fermentation is shown in Fig. 2. Theoretically, one mole of glucose can be converted to one mole of butanol (0.41 g g−1 ), one mole of acetone (0.32 g g−1 ) or two moles of ethanol (0.51 g g−1 ). Typically, the ABE yield in the real situation is further decreased by production of biomass, acetic and butyric acids left unreassimilated, and carbohydrates like granulose. Details of metabolic pathways and biochemistry of clostridial species are well documented in other review papers (Jones and Woods 1986; Durre 2007; Cho et al. 2015b). Before the advent of metabolic engineering tools for clostridia, many studies were conducted on developing gene manipulation system and better understanding of complex metabolism of clostridia (Jones and Woods 1986; Oultram et al. 1988; Wiesenborn, Rudolph and Papoutsakis 1989; Young, Minton and Staudenbauer 1989; Mermelstein et al. 1992; Lee, Bennett and Papoutsakis 1992a; Lee et al. 1992b). In 1992, the first metabolic engineering of clostridia appeared when the B. subtilis–C. acetobutylicum shuttle vector pFNK1 was constructed and used to successfully overexpress acetoacetate decarboxylase (adc) and phosphotransbutyrylase (ptb) genes in C. acetobutylicum ATCC 824 (Mermelstein et al. 1992). Since genetic manipulation is easiest in Escherichia coli, the use of E. coli–C. acetobutylicum shuttle vectors was thought to be more desirable for their use in C. acetobutylicum. Due to the strong restriction system in C. acetobutylicum, however, such E. coli–C. acetobutylicum vectors could not be introduced until Mermelstein and Papoutsakis (1993) developed a breakthrough method of employing the 3T I methyltransferase of B. subtilis phage 3T. The methylation of DNA using this methyltransferase was able to protect the recombinant plasmids from Cac824I restriction endonuclease in C. acetobutylicum (Lee et al. 1992b; Mermelstein and Papoutsakis 1993). Thanks to this discovery and development, further metabolic engineering of C. acetobutylicum has become possible. For example, the acetoacetate decarboxylase (adc) and CoA transferase (ctfAB) genes were overexpressed on the basis of plasmid pFNK6 in C. acetobutylicum. The metabolically engineered C. acetobutylicum strain demonstrated increased solvent production by 50% with production of 13 g L−1 of butanol (Mermelstein et al. 1993). Manipulation of the genome in clostridial species has shown to be more challenging compared to vector-borne gene overexpression. Wilkinson and Young (1994) first reported the targeted inactivation of the C. beijerinckii spo0A gene using Campbelllike integration. Similarly, Green et al. (1996) reported two different knockout mutant strains of C. acetobutylicum. Among them, the buk mutant C. acetobutylicum PJC4BK strain produced 10.8 g L−1 of butanol from glucose in a batch fermentation, which was higher than that (9.7 g L−1 ) produced by

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Figure 2. Major metabolic pathways and enzymes involved in clostridial ABE fermentation. Major products in the solventogenic phase are shown in black boxes, while those mainly produced in the acidogenic phase are shown in gray boxes.

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wild-type ATCC 824 (Green et al. 1996). In later studies, improved fermentation of the PJC4BK strain resulted in production of 16.7 g L−1 of butanol (Harris et al. 2000). Also, the use of antisense RNA has been examined to knockdown genes of interest for metabolic engineering of C. acetobutylicum (Desai, Nielsen and Papoutsakis 1999). The next notable advancement in metabolic engineering was the first use of mobile group II intron in clostridia due to its convenience and higher efficiency as demonstrated by several groups (Heap et al. 2007; Shao et al. 2007; Jang et al. 2012b, 2013b, 2014b; Mohr et al. 2013; Wang et al. 2013). Using this method, mutants having multiple gene disruptions were successfully developed. The C. acetobutylicum BEKW(pPthlAAD∗∗ ) strain was developed by in silico genome-scale metabolic simulation and multiple chromosomal manipulations (Jang et al. 2012b). It was demonstrated that acid production could be greatly reduced by double disruption of the pta and buk genes (the BEKW strain). Butanol production was further reinforced through the so called hot-channel by the overexpression of the adhE1D485G gene, encoding alcohol dehydrogenase capable of utilizing both NADH and NADPH as cofactors, in the BEKW strain. The resulting BEKW(pPthlAAD∗∗ ) strain produced 18.9 g L−1 of butanol with a yield of 0.29 g g−1 glucose in a batch fermentation. Through the integration of in situ recovery using polymeric resins with fermentation, 585.3 g of butanol was produced from 1861.9 g of glucose with a yield of 0.31 g g−1 glucose and a productivity of 1.32 g L−1 h−1 (Jang et al. 2012b). This method was similarly used in other species such as C. beijerinckii NCIMB 8052 (Wang et al. 2013); the buk gene disrupted C. beijerinckii strain produced 12.7 g L−1 of butanol with a yield of 0.24 g g−1 glucose in a batch fermentation. In addition to manipulating the fermentation pathway itself, several studies have demonstrated improved butanol production by manipulating the genes other than those directly involved in ABE biosynthetic pathways, including modifications of regulatory genes (Nair et al. 1999; Xu et al. 2015), stress response (Tomas, Welker and Papoutsakis 2003) and glycolysis (Ventura, Hu and Jahng 2013). Papoutsakis group demonstrated that solR might act as a repressor of the sol operon in C. acetobutylicum (Nair et al. (1999). Two knockout strains called B and H, were found, and the mutant B was shown to produce 17.8 g L−1 of butanol, much higher than that produce by the wild-type strain. In a subsequent study, the adhE1 gene was overexpressed in another solR mutant H strain, resulting in production of 17.6 g L−1 of butanol from glucose in a batch fermentation, which was higher than that (14.6 g L−1 ) obtained from the batch fermentation of the mutant H strain itself (Harris et al. 2001). However, the role of solR still remains unclear, as another study suggested that the product of this gene did not exhibit any DNA binding activity in vitro (Thormann and Durre 2001). In another study, overexpression of the groESL gene in the C. acetobutylicum ATCC 824 resulted in the butanol production of 17.1 g L−1 from glucose in a batch fermentation (Tomas, Welker and Papoutsakis 2003), possibly due to improved protein folding against butanol stress. There have been few studies on manipulation of the glycolytic pathway. Recently, 6phosphofructokinase (pfkA) and pyruvate kinase (pykA) genes were overexpressed in C. acectobutylicum with an aim to increase ATP and NADH levels (Ventura, Hu and Jahng 2013). The resulting strain showed increased butanol production of 19.1 g L−1 with a yield of 0.21 g g−1 from glucose in a fed-batch fermentation (Ventura, Hu and Jahng 2013). Also, the deletion of the cac3319 gene encoding histidine kinase led to an enhancement on butanol production. The resulting C. acetobutylicum HKKO strain

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produced 18.2 g L−1 of butanol with a yield of 0.20 g g−1 glucose in a batch fermentation (Xu et al. 2015). Owing to the complex regulation of solventogenesis, the use non-solventogenic clostridial strains has also been examined. Most studies have been demonstrated using degenerate strains of C. acetobutylicum (Nair and Papoutsakis 1994; Sillers et al. 2008; Lee et al. 2009). However, butanol titers reported were typically lower in the engineered degenerate strains. Recently, a hyperbutyrate producing strain C. tyrobutyricum has also been metabolically engineered to produce butanol, because C. tyrobutyricum has relatively higher butanol tolerance (Liu, Zhu and Yang 2006; Yu et al. 2011). Using an E. coli-Clostridium shuttle plasmid carrying the pIM13 replicon, the bifunctional aldehyde/alcohol dehydrogenase gene (adhE2) from C. acetobutylicum was introduced into an acetate kinase mutant of C. tyrobutyricum. The resulting C. tyrobutyricum strain produced 10.0 g L−1 and 16.0 g L−1 butanol from 37 g L−1 glucose and 53 g L−1 of mannitol, respectively, in batch fermentations (Yu et al. 2011). When the pIM13 replicon was replaced with the pBP1 replicon for the expression of the adhE2 gene, 20.5 g L−1 of butanol was produced with a yield of 0.33 g g−1 mannitol in fed-batch fermentation (Yu et al. 2012). Additionally, maltose-utilizing C. tyrobutyricum strains were developed by individually introducing the agluI and agluII genes encoding α-glucosidases into the C. tyrobutyricum ack-adhE2 strain. The metabolically engineered C. tyrobutyricum (ack)-pGluI strain produced 17.3 g L−1 butanol with a yield of 0.17 g g−1 maltose in batch fermentation (Yu et al. 2015). The complete genome sequence of C. acetobutylicum ATCC 824 was determined about 15 years ago (Nolling et al. 2001), which has been used as a vital resource on further understanding and metabolic engineering of C. acetobutylicum. Availability of the complete genome sequence led to the development and use of other techniques, such as omics technologies and in silico genome-scale metabolic network modeling and simulations (Papoutsakis 1984; Gorwa, Croux and Soucaille 1996; Desai et al. 1999; Desai, Nielsen and Papoutsakis 1999; Lee et al. 2008a; Senger and Papoutsakis 2008a,b; Jang et al. 2014a; Cho et al. 2015b). Thanks to the advent of next-generation sequencing methods, the genome sequences of other solventogenic clostridia have also become available. Since there are still many unknown mechanisms in solventogenic clostridia, including TCA cycle (Amador-Noguez et al. 2010; Crown et al. 2011), initiation of solventogenesis and its relationship to sporulation (Bi et al. 2011; Al-Hinai, Jones and Papoutsakis 2015), comparative analyses of these clostridial genomes will make it possible to better understand the physiological characteristics to develop novel metabolic engineering strategies. As discussed above, clostridial strains are extremely difficult to genetically engineer. One of the reasons is the low efficiency of homologous recombination, possibly due to the lack of Holliday junction resolvase. To overcome this problem, several approaches have been demonstrated, including complementation of Holliday junction resolvase (Jones et al. 2011; Tracy, Jones and Papoutsakis 2011), allele-coupled exchange (Heap et al. 2012), recombineering (Dong et al. 2014) and CRISPR-mediated double strand break to induce homologous recombination (Wang et al. 2015). Even though it is still difficult and time-consuming to achieve multiple chromosomal manipulations of clostridia compared to other species, better tools and methods will be developed through continued effort in the near future. When gene knockout becomes difficult due to several possible reasons including gene essentiality, gene knock-down methods such as that using antisense RNA (Desai, Nielsen and Papoutsakis 1999) and synthetic small RNAs (Na et al. 2013) can be employed. Such

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Table 2. Major bottlenecks of clostridial butanol fermentation and approaches to address them. Issues

Approaches

Raw material (substrate) cost

(i) The use of new host that can utilize cheaper substrates and even carbon dioxide (e.g. acetogens and cellulolytic clostridia) (ii) Development of physical/chemical pretreatment processes that do not require expensive enzymatic treatment (iii) Introduction of novel substrate utilizing pathways into the production host

Low titer, yield and productivity

(i) Development of asporogenic strains for higher cell density (ii) Improvement of butanol tolerance and other toxic compounds present in cheap substrates (e.g. furfural and phenolics in lignocellulosic hydrolysates) (iii) The use of immobilization or cell recycling processes (iv) Optimization of the growth medium for prolonged fermentation (v) Metabolic engineering for developing superhost strain capable of producing butanol to the level of phase separation (vi) Phage-resistant strains for long-term stability of fermentation

Poor genetic engineering tools

(i) Development of more plasmid vectors and more efficient transformation methods (ii) Development of more efficient gene knockout methods (e.g., CRISPR-Cas system) (iii) Development of inducible expression systems with stringent control (iv) Development of conditionally replicating plasmids for multiple chromosomal manipulations

Poor understanding on physiology

(i) Detailed characterization and understanding of acidogenic and solventogenic phases and phase transition (ii) Better measurement of metabolic fluxes under various conditions for characterizing metabolism (iii) Better understanding on complex regulatory circuits and their interactions with metabolism

methods can be applied to not only more efficient metabolic engineering, but also to development of phage-resistant strains, which is another important goal for industrial-scale fermentations, by mutating phage integration sites in the genome (Jones et al. 2000). Further, advances in metabolic engineering strategies and development of methods allowing higher efficiency transformation, conditionally replicating plasmids and more efficient gene knockdown and knockout will speed up the metabolic engineering of clostridia for the enhanced production of butanol.

CONCLUSIONS Over the past 100 years, much advancement has been made in the production of butanol using the genus Clostridium. Innovative fermentation techniques were extensively investigated, including aspects such as multistage, coculture, immobilization and cell recycling while also focusing on minimizing production costs by investigating inexpensive substrates. Further, advances were made in order to overcome the susceptibility of the clostridia to butanol toxicity, including extensive studies utilizing the in situ recovery technologies and methodologies. In more recent studies, strain development through metabolic engineering has been actively explored for enhanced production of butanol. It is expected that more advanced genome and metabolic engineering tools will be developed for manipulating clostridial strains. Through the 100 years of investigations, butanol production and productivity reached 25.7 g L−1 in batch fermentation and 10.7 g L−1 h−1 in continuous fermentation, respectively (Table 1). Moreover, production of 585.3 g of butanol has been demonstrated in fed-batch fermentation with in situ recovery by adsorption (Jang et al. 2012b). In revived industrial butanol fermentation processes in operation in countries like China, batch fermentation using a high initial concentration of substrate is still a common practice for butanol production, but repeated

fed-batch and semicontinuous cultivation methods are also under operation. Based on the performance indices reported, the current fermentative butanol production cost is estimated to be US$0.8 ∼ 2 per kg of butanol depending on the raw materials. Compared to the typical fermentation results of 9–14 g L−1 of butanol with productivities of 0.11–0.33 g L−1 h−1 using wildtype strains in batch fermentation, these results indeed showcase great achievements made over the last 100 years (Table 1). Major bottlenecks to be overcome in the future are summarized in Table 2. Also, detailed regulatory mechanisms involved in acidogenesis and solventogenesis in the context of overall carbon fluxes are expected to be revealed; a recently discovered redox-switch regulatory mechanism of clostridial thiolase (Kim et al. 2015) is a good example. Integration of systems metabolic engineering strategies with fermentation and downstream processes (Lee et al. 2012b; Lee and Kim 2015; Yoo et al. 2015) will further improve the overall performance of clostridial butanol production. Although not mentioned in detail in this manuscript, problems of phage infection in the industrial-scale fermentation will also be addressed. In addition, there has been much effort exerted to develop non-clostridial microorganisms including yeast and Escherichia coli for enhanced butanol production, which deserves attention. The last 100 years of clostridial butanol fermentation have seen significant advances in all aspects, from strain development, fermentation and downstream processes. It is expected that clostridial fermentative butanol production in large-scale will be revived in the near future, even in the era of low or fluctuating oil price, to cope with climate change and other environmental issues.

ACKNOWLEDGEMENTS We thank Jaesung Cho, Kyeongrok Choi, Dongsoo Yang and Junho Bang for valuable comments during the preparation of this manuscript.

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FUNDING This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science, ICT and Future Planning (MSIP) through the National Research Foundation (NRF) of Korea (NRF-2012-C1AAA001-2012M1A2A2026556) and by the C1 Gas Refinery Project (2015M3D3A1A01064918) funded by the MSIP through the NRF of Korea. Conflict of interest. None declared.

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